AU2020272151B2 - Process for continuous production of an active ingredient granulate - Google Patents

Abstract

A process for continuous production of an active ingredient granulate is provided and comprises the following steps: (a) providing a spraying composition by dissolving or dispersing an active ingredient and optionally one or more auxiliaries in a liquid; (b) providing solid particles in a process space; (c) introducing droplets of the spraying composition into an injection zone of the process space in which the liquid is evaporated; (d) repeatedly running the solid particles past spray-introduced droplets in the process space using a process gas jet, so that at least a proportion of the droplets, which may already have lost a portion of the obtained liquid, comes into contact with solid particles, thus forming larger solid particles by agglomeration; (e) withdrawal of the active ingredient granulate from the process space in the form of solid particles, wherein the active ingredient comprises metformin or an acid addition salt of metformin, in particular metformin hydrochloride.

Description

1

Process forthe Process for thecontinuous continuous production production of anof an active active ingredient ingredient granulate granulate

Description Description

Field Field of of invention invention

Theinvention The inventionrelates relatestotoa amethod methodforfor thethe continuous continuous production production of active of active ingredient ingredient

granules,the granules, thegranules granules themselves themselves anduse. and their their Theuse. The invention invention also also relates to relates to controlled controlled release dosage release dosage forms. forms. Metformin Metformin andacid and its its addition acid addition salts, salts, especially especially metformin metformin

hydrochloride, hydrochloride, areare used used asactive as the the active ingredient. ingredient.

Backgroundofofthe Background theinvention invention

After production After production andand purification, purification, active active pharmaceutical pharmaceutical ingredients ingredients areobtained are usually usually obtained in a in formthat a form thatrequires requires extensive extensive further further processing processing steps insteps order in to order converttothe convert active the active ingredientinto ingredient intoa adosage dosage form. form. In particular, In particular, the active the active ingredient ingredient is not is often often not obtained obtained in in the form the formofofparticles particlesthat thatcancan be be readily readily formulated. formulated.

Thenecessary The necessary work-up work-up steps steps include include comminuting, comminuting, grinding, grinding, sieving sieving andlike. and the the like. It It is is also known also knownto to produce produce active active ingredient ingredient powders powders by spray-drying by spray-drying active ingredient active ingredient

solutions. solutions.

As aa rule, As rule, however, active ingredient however, active ingredient powders alsohave powders also havetotobebefurther furtherprocessed processed before before

the production the production of of dosage dosage forms, forms, such such as tablets, as tablets, is possible, is possible, becausebecause finelyforms finely divided divided forms of active of activeingredients ingredientshave have processing processing disadvantages. Thesedisadvantages disadvantages. These disadvantages often often include include

a lack a lackof of flowability. flowability. Another Another disadvantage disadvantage is fine is that that powders fine powders often often have poorhave poor stability. stability. Theytend They tendtoto aggregate aggregateand and clump. clump.

In In order toavoid order to avoidsuch such disadvantages, disadvantages, it is customary it is customary to provide to provide granules.granules.

Granuleswhich Granules whichcontain containanan activeingredient active ingredientand and optionallyone optionally one or or more more excipients excipients cancan

be used be usedtotoproduce produce dosage dosage forms, forms, for for example example by pressing by pressing themtablets them into into tablets alone alone or or togetherwith together withother other components. components. Active Active ingredient-containing ingredient-containing particles particles can also becan also filled be filled into capsules into capsules oror used used in the in the form form of aof a powder powder for a suspension for a suspension or solution. or solution. They They can also can also be provided be providedwith with coatings. coatings.

A number A numberofofprocesses processes are are known known forfor thethe production production of of granules.These granules. These processes processes often often

operate as operate as batch batch processes. processes.A Apreprocessed, preprocessed,usually usuallyground ground andand sieved sieved active active

ingredientisisused. ingredient used.

Theproperties The propertiesofofthe thegranules granulesobtained obtained areare notnot always always satisfactory, satisfactory, in in particularwith particular with regardtotoflowability regard flowabilityand and stability. stability.

Theprior The prior art art also alsocontains contains proposals proposals to to produce granulesusing produce granules usingspouted spoutedbed bed apparatus. apparatus.

It It is is known fromDEDE known from 103 103 22 A1 22 062 062 to A1 to produce produce granules granules of different of different materialsmaterials by by

2 introducing liquids introducing liquids into into aasolids solidsflow flowof ofa spouted a spouted bed apparatus. bed apparatus. However,However, the the application mentioned application mentioneddeals deals neither neither with with thethe particularitiesofofpharmaceutical particularities pharmaceutical active active

substancesnor substances norwith withthe theconditions conditionsthat that are are suitable suitable for forprocessing processing such substances. such substances.

DE100 DE 1000404939 939C1C1 relates relates totoa acontrollable controllable gas gasinflow inflow device device for for spouted bedapparatus. spouted bed apparatus.

WO WO 2004/108911 2004/108911 A2 describes A2 describes manufacturing manufacturing processes processes for enzyme for enzyme granules granules and the and the granules of granules of this this type. type. A A spouted bedapparatus spouted bed apparatusis is used used forfor production. production. The The application application

doesnot does notdeal deal with with thethe production production of tablets of tablets or theor the ability ability of theofgranules the granules to be tableted. to be tableted.

WO2008/110374 WO 2008/110374 A2 relates A2 relates to pellets to pellets containing containing a pharmaceutical a pharmaceutical substance substance with a with a breaking strength breaking strengthofofmore more than than 0.001 0.001 newtons, newtons, processes processes forproduction for their their production and and pharmaceuticalpreparations pharmaceutical preparationsbased based on on such such pellets. pellets. It It isisshown shown that that spherical spherical mannitol mannitol

pellets with pellets with aauniform uniformparticle particlesize size grain grain distribution distribution andand smooth smooth surface surface can be produced can be produced

from aa mannitol from mannitolsolution solutionand andthat thatsuch suchpellets pelletscan canbebe coated coated with with an an active active ingredient ingredient

layer by layer bylayering layeringthethe active active ingredient. ingredient.

While the While the above abovedocuments documents contain contain no no reference reference to to metformin, metformin, thethe production production of of dosage dosage

forms which forms which contain contain metformin metformin oracid or its its addition acid addition salts, salts, in particular in particular metformin metformin

hydrochloride, is hydrochloride, is the the subject subject of ofnumerous patent applications numerous patent applications and andpublications. publications.

O.R. Arndt O.R. Arndt and andP. P. Kleinebudde, Kleinebudde,AAPS AAPS PharmSciTech. PharmSciTech. 2018 2018 Jul;(5): Jul; 19 19 (5): 2068-2076, 2068-2076, pointpoint

out that out that metformin haspoor metformin has poor tabletingproperties tableting propertiesandand poor poor flowabilityandand flowability is is therefore therefore

typically wet-granulated typically with a abinder wet-granulated with binderbefore before tableting. tableting. However, However, this this is viewed is viewed as as disadvantageous disadvantageous because because of the of the associated associated costs. costs. A dryAprocess dry process by of by means means rollerof roller compactionisistherefore compaction therefore proposed. proposed.

US Pat. No. US Pat. No. 6,667,054 6,667,054B2B2describes describestablets tabletswhich whichcontain containmetformin metformin hydrochloride.They hydrochloride. They are made are froma adry made from drymixture mixtureofofmetformin metformin hydrochloride hydrochloride andand methyl methyl cellulose. cellulose.

No. 6,117,451 No. 6,117,451describes describesa amixture mixtureofofa acrystalline crystalline metformin metforminhydrochloride hydrochloridepowder powder andand

powderedexcipients powdered excipientswhich which can can be be pressed pressed directly directly intotablets. into tablets.

H. Takasaki H. Takasakietetal., al., Results ResultsininPharma Pharma Sciences Sciences 5 (2015) 5 (2015) 1-7 describe 1-7 describe a moisture- a moisture-

activated dry activated dry granulation granulation of of metformin hydrochloride. metformin hydrochloride.

B.S. Barot B.S. Barot et et al ., Acta al., ActaPharm. Pharm. 60 60 (2010) (2010) 165-175, point out 165-175, point out that that metformin metformin hydrochloride hydrochloride

is hygroscopic is andhas hygroscopic and hasstability stability problems, problems,and anddescribe describe thethe development development of a of a directly directly

compressiblemetformin compressible metformin hydrochloride hydrochloride by spray by spray drying. drying. This This leads leads to a product to a product with with approximately approximately spherical spherical particles particles whichwhich are typically are typically less less than 50 than µm in50 um µm in diameter. diameter.

In In addition, addition,studies studieshave havebeen been carried carriedout outon onthe therelease releaseofof metformin metforminfrom fromdosage dosage forms forms

in order in todetermine order to determine where where in theingastrointestinal the gastrointestinal tract tract the the ingredient active active ingredient should be should be

3

releasedininorder released order to to achieve achieve a good a good effect.effect. In particular, In particular, it has it hassuggested been been suggested that the that the release is release is only only particularly particularlyadvantageous in deeper advantageous in deeperintestinal intestinal sections sections (H. (H. Schatz, Schatz, New New

Findings Findings on on Metformin Metformin (2016). (2016).

https://www.diabsite.de/aktuelles/nachrichten/2016/160503b.html https://www.diabsite.de/aktuelles/nachrichten/2016/160503b.html ). ). https://www.diabsite.de/aktuelles/nachrichten/2016/160503b.html).

Regardless Regardless ofofall all these theseproposals, proposals,there thereisisstill still aa need for improved need for improvedmethods methods for for the the

production of production of dosage formscontaining dosage forms containingmetformin. metformin.

Objects and Objects and summary summary ofofthe theinvention invention

Oneobject One objectofofthe theinvention invention is is to to provide a continuous provide a continuousmethod methodforfor the the production production of of an an

active substance active granulate,the substance granulate, theactive activesubstance substance being being an an active active substance substance with with poor poor

flowability. The flowability. Themethod should enable method should enableaahigh highthroughput throughputand anda ahigh highyield yieldwith with adjustable adjustable granulateproperties granulate properties (such (such as particle as particle diameter, diameter, moisture, moisture, bulk density). bulk density).

Anotherobject Another object is is to to provide provide a method a method whichitmakes which makes it to possible possible to adjust adjust the the particle particle size size of the of granulateparticles. the granulate particles.

A further A furtherobject objectofofthethe invention invention is produce is to to produce granulate granulate particles particles whichatcontain which contain least at least oneactive one activeingredient ingredient andand which which exhibit exhibit good flowability. good flowability.

In addition, itit is In addition, is an objecttotoprovide an object provide granules granules with with a level a high high of level of stability. stability. In particular, In particular,

the granulate the particles should granulate particles should not not aggregate or clump aggregate or clumptogether. together.

Anotherobject Another objectis is to to provide a method provide a methodfor forproducing producinga asemi-finished semi-finished product, product, thethe semi- semi-

finished product finished product consisting consistingofofanan active active ingredient ingredient and and at least at least one excipient one excipient and and preferablybeing preferably being able able to further to be be further processed processed into tablets. into tablets.

It It is isalso also an an object to provide object to providea amethod method for producing for producing tablets. tablets.

Finally, Finally,one one object object is isto toprovide providedosage formswith dosage forms with controlled controlled release releaseand andmethods methodsforfor

their production, their production, in in particular particulardosage dosage forms whichonly forms which onlyrelease releasethe theactive activeingredient ingredientinin deepsections deep sections of of thethe intestine, intestine, suchsuch asileum as the the ileum or the or the colon. colon.

Accordingtotothe According the invention, invention, it it has has now beenfound now been foundthat thatthe thecontinuous continuous production production of of an an

active ingredient-containing active ingredient-containing granulate granulate is possible is possible by introducing by introducing droplets droplets of a or of a solution solution or suspensioncontaining suspension containing the the active active ingredient ingredient intoa process into a process space space in which in which the liquid the liquid

evaporates,the evaporates, the droplets droplets being beingguided guidedwith withthe thehelp helpof of aa suitably suitably temperature-controlled temperature-controlled

processgas process gassosothat thatparticles particles that that are are already alreadyinin the the process processspace space come come intointo contact contact

with droplets with droplets that that still still contain containatatleast leastenough enough liquid liquid so so that that they they are are attached to the attached to the particles. particles.

Themethod The method according according to invention to the the invention forcontinuous for the the continuous production production of an of an active active ingredient granulate ingredient granulate accordingly comprisesthe accordingly comprises thefollowing followingsteps: steps:

4 (a) (a) preparing a spray preparing a spray composition compositionbybydissolving dissolvingorordispersing dispersinganan activeingredient active ingredientand and optionallyone optionally oneorormore more excipients excipients in a liquid; in a liquid;

(b) (b) providing solidparticles providing solid particlesinina aprocess process space; space;

(c) (c) introducing introducing droplets droplets of of the the spray spray composition into an composition into an injection injection zone of the zone of the process process spacein space in which whichthe theliquid liquid evaporates; evaporates;

(d) (d) repeated guiding repeated guiding of of thethe solid solid particles particles pastpast the sprayed the sprayed droplets droplets in the process in the process space space with the with the aid aid of of a a process gasjet, process gas jet, so so that that at at least least aa portion portion of ofthe thedroplets, droplets,which which may may

havealready have already lost lost part part of of thethe liquid liquid contained, contained, comescomes into contact into contact with with solid solid particles particles and and larger solid larger solidparticles particlesare formed are formedthrough through agglomeration; agglomeration;

(e) (e) removing the active removing the active ingredient ingredient granulate from the granulate from the process processspace spaceininthe theform formofofsolid solid particles, particles,

whereinthe wherein the active active ingredient ingredient comprises metforminororananacid comprises metformin acidaddition additionsalt salt of of metformin, metformin,

in particular in metformin particular metformin hydrochloride. hydrochloride.

In In contrast tothe contrast to theproduction production of particles of particles by spray by spray drying drying in a conventional in a conventional spray tower, spray tower,

according according to to the the invention, invention, the the particles particles formed formed are circulated are circulated in the process in the process space space until until they have they havereached reached the the desired desired size size through through repeated repeated agglomeration agglomeration of droplets of droplets of of the the solutionorordispersion solution dispersionandand evaporation evaporation of the of the liquid. liquid.

In In the the method according method according toto theinvention, the invention,the thegrowth growthof of the the particlescan particles cantherefore thereforebebe controlled. controlled.

Thegranulate The granulateobtained obtainedcan can bebe processed processed intointo tablets. tablets. Compared Compared to known to known granulates, granulates,

it has it improved has improved properties, properties, in particular in particular withwith regard regard to stability to stability and flowability. and flowability.

Thegranules The granulescan can also also be be processed processed into into coated coated dosagedosage forms, forms, in particular in particular dosage dosage

formswhich forms which only only release release the active the active ingredient ingredient in the in theorileum ileum or colon. colon.

Brief Brief description ofthe description of thefigures figures

Theinvention The inventionis is explained explained in more in more detaildetail below below with reference with reference to to figures. figures.

In In Fig. Fig. 1, 1, a systemfor a system forperforming performingthethe method method according according to thetoinvention the invention is shown is shown

schematically. schematically.

Fig. 2 shows Fig. 2 shows a typical a typical particle particle size size distribution. distribution.

Fig, Fig, 33 shows shows aa micrograph micrographofofaatypical typical sample. sample.

Fig. Fig. 44 shows shows aa micrograph micrographofofaafurther further sample. sample.

Detailed descriptionofofthe Detailed description theinvention invention

5 Thegranulate The granulate particles particles produced produced according according to the invention to the invention contain contain an an active ingredient. active ingredient.

Theactive The activeingredient ingredient comprises comprises metformin metformin or one ofor one its ofaddition acid its acidsalts, addition salts, in in particular particular metformin hydrochloride. metformin hydrochloride. According to one According to one embodiment, embodiment,thetheactive activeingredient ingredient isis metformin metformin or or oneone of its of its acid acid addition addition salts, salts, in particular in particular metformin metformin hydrochloride. hydrochloride.

Accordingtoto one According oneembodiment, embodiment,thethe granulate granulate particles particles consist consist ofofthe theactive activeingredient. ingredient.

In In addition tothe addition to theactive activeingredient, ingredient, thethe granulate granulate particles particles cancontain can also also contain one or more one or more

excipients. Any excipients. pharmaceuticallysuitable Any pharmaceutically suitableexcipient excipient cancan be used be used as anas an excipient. excipient. In In particular, excipients particular, excipientsareare used used thatthat are are typically typically used used forproduction for the the production of granules of granules and and tablets. Exemplary tablets. Exemplary excipients excipients are binders, are binders, lubricants, lubricants, disintegrants disintegrants and and fillers. fillers.

A preferred A preferred auxiliary auxiliary is is a binder. a binder. Binders Binders promote promote the of the binding binding of the granulate the granulate particles particles duringtableting. during tableting.

In oneembodiment, In one embodiment,theythey also also support support the formation the formation of the of the granulate granulate particles, particles, in in particular when particular when active active ingredient ingredient is wholly is wholly or partially or partially dispersed dispersed in the in the liquid. liquid.

Exemplarybinders Exemplary binders are polyvinylpyrrolidone are polyvinylpyrrolidone (PVP), (PVP), vinylpyrrolidone-vinyl vinylpyrrolidone-vinyl acetate acetate copolymers,hydroxypropyl copolymers, hydroxypropyl cellulose(HPC) cellulose (HPC)andand hydroxypropyl hydroxypropyl methylcellulose methylcellulose (HPMC). (HPMC).

PVP PVP isis preferred. preferred.

Thebinder The bindercan canbebeused, used,for forexample, example,in in anan amount amount of 0.1 of 0.1 to to 10% 10% by weight, by weight, preferably preferably

1 to 7% 1 to 7% byby weight weight andand in particular in particular 2.55%toby5% 2.5 to by weight, weight, based based on onmatter the dry the dry matter content. content.

In In the the method accordingtotothe method according theinvention, invention, aa spray spray composition compositionisis sprayed sprayedinto intoaa process process space. The space. Thespray spraycomposition compositionis isa asolution solutionororaa suspension. suspension.

Anyliquid Any liquidwhich which does does not react not react ornot or does does nottoreact react to a significant a significant extent extent with with the active the active substanceand substance and which which cancan be removed be removed under under conditions conditions which which do not do notorlead lead doesor does not not lead to lead to any significant extent any significant extenttotothe thedecomposition decomposition of of the the active activesubstance can be substance can beused used as the as theliquid liquidfor for preparing preparingthethe solution solution or suspension. or suspension.

A preferred A preferredliquid liquidcontains contains water. water. In particular, In particular, the liquid the liquid is water. is water.

Thespray The spraycomposition composition contains contains the active the active ingredient ingredient and optionally and optionally one one or more or more excipients. The excipients. spraycomposition The spray composition preferably preferably contains contains a high a high concentration concentration of active of active

ingredientand ingredient and / orexcipients. / or excipients.

Thespray The spraycomposition composition can can also also contain contain ingredients ingredients in in undissolved undissolved form. form. In In a preferred a preferred

embodiment, embodiment, the the saturationsolubility saturation solubility of of one one or or more of the more of the constituents constituents is isexceeded, so exceeded, so

that aa suspension that is present. suspension is present.

6 Withaahigh With highdrydry matter matter content content in spray in the the spray composition, composition, lesshas less liquid liquid has to be to be evaporated evaporated

to obtain to thedesired obtain the desired solid solid particles, particles, allowing allowing higher higher throughput. throughput. A highAdry high dry matter matter content content is therefore is preferred.ItItisisalso therefore preferred. alsopreferred preferredto to useuse a suspension. a suspension.

Thedry The drymatter mattercontent content of of the the spray spray composition composition is typically is typically at at least least 25%25% by weight, by weight,

preferably at preferably at least least 40% 40%by by weight, weight, in particular in particular at least at least 50% 50% by weight by weight and and most most preferably at preferably at least least65% by weight. 65% by weight.

Thedry The drymatter matter content content relates relates tototal to the the total weightweight of the of the used, solids solidsrelative used, relative to the to the total total weight of weight of the the spray spray composition. composition.

Theproportion The proportionof of thethe active active ingredient ingredient indry in the thematter dry matter contentcontent is typically is typically at leastat least 70% 70% by weight, by weight,preferably preferably at least at least 80% 80% by weight by weight and in particular and in particular at least at 90%least 90% It by weight. by weight. It can be can be100% 100%by by weight. weight.

In In the the method method ofofthe theinvention, invention,droplets dropletsare areformed formed from from the the spray spray composition. composition. The The

droplets from droplets the solution from the solution or or suspension are flowable. suspension are flowable.

In In the the process spacethey process space theylose loseliquid liquiddue duetotoevaporation. evaporation.Small Small solid solid particlescan particles canbebe formedfrom formed fromthe thedroplets. droplets.

It It is ischaracteristic of the characteristic of the method method according according to thetoinvention, the invention, however, however, that particles that particles that that are already are alreadyininthe theprocess process space space come come into into contact contact with droplets with droplets that stillthat still contain contain at least at least enoughliquid enough liquid so sothat that they they are are attached attachedtotothe theparticles. particles. When When inincontact contactwith withthe thesolid solid particles, the particles, the droplets dropletsmust must stick stick together together at least at least onsurface. on the the surface.

Suchanan Such attachment attachment allows allows particles particles of sufficient of sufficient size tosize to be formed. be formed.

To this To this end, end, it it isisessential essentialthat thatthe theagglomeration agglomeration of of the the particles particlesisismade possible by made possible by previouslyintroduced previously introduced particles, particles, i.e. i.e. particles particles already already introduced introduced into theinto the space process process space in solid in solidform, form,or orparticles particlesformed formedby byspraying spraying in infrom from the thespray spray composition, composition, repeatedly repeatedly

cominginto coming intocontact contactwith withdroplets droplets of of thethe spray spray composition, composition, so that so that aggregates aggregates are are formed. The formed. Thesolid solid particles particles produced accordingtotothe produced according theinvention invention are are typically typically aggregates aggregates

of globules of thatare globules that are firmly firmly connected connected toanother. to one one another.

In In the the method according method according to to the the invention,thethe invention, particlesare particles aremoved moved within within the the process process

spacewith space with thethe aidaid of of thethe process process gaswhich gas jet, jet, which is guided is guided in a defined in a defined manner, manner, so that a so that a circulating flow circulating flowofofsolids solidsisisgenerated. generated.TheThe flowflow of solids of solids leadsleads intoarea into the theofarea the of the device device (injection zone) (injection zone)ininwhich which droplets droplets thatthat can can be attached be attached to solidtoparticles solid particles are introduced. are introduced.

Accordingtoto one According oneembodiment, embodiment, particles particles thathave that have reached reached a desired a desired sizesize cancan leave leave the the

processspace. process space.Smaller Smallerparticles particles remain remaininin the the process processspace spacesosothat thatthey theycan cancome come into into

contact with contact with droplets droplets again. again. According Accordingtotoanother another embodiment, embodiment, a portion a portion of solid of the the solid

7 particles is particles is removed fromthe removed from theprocess process space. space. The The removed removed material material is classified is classified and and small particles small particles can be returned can be returnedtotothe theprocess processspace. space. Excessively Excessively large large particles particles cancan

also be also returned to be returned to the the process area after process area after being comminuted. being comminuted.

Theprocess The processgasgas can can be,example, be, for for example, air or air or angas an inert inert gas such as such as nitrogen, nitrogen, carbon carbon dioxide dioxide or or aa or noble a noble gas. noblegas. gas.

Theprocess The processgas gas jet jet is essential is essential bothboth for transport for the the transport of substances of substances andtransport and for the for the transport of heat. of heat. According to the According to the invention, invention, the the temperature temperatureofofthe theprocess processgasgas jetjetisisselected selected suchthat such thatthe thesprayed sprayed droplets droplets comecome into contact into contact with particles with particles that already that have have already solidified, with solidified, with the formationofoflarger the formation largerparticles. particles.InInparticular, particular,such such temperature temperature conditions conditions

are provided are providedin in the the process processspace space thatthe that theproduct product is isnot notexposed exposed to any to any temperature temperature

conditionsthat conditions thatimpair impair itsits stability,butbut stability, on on the the other other hand hand sufficient sufficient drying drying is ensured is ensured by by evaporation evaporation of of liquid. liquid.

Theprocess The processgas gas jetjettypically typically has hasaatemperature temperaturein in the the range range from from 60 100 60 to to 100 o C.C.° The The C. The product temperature product temperatureisistypically typically 30 30 to to 60 60 °C. C.

Theprocess The processgas gasjet jet preferably preferably has has aa temperature temperatureinin the the range rangefrom from70 70to to 90.degree. 90.degree.The 0.degree. The The

product temperature product temperatureisispreferably preferably 35 35to to 50 50 C. ° C.

In In a a particularly particularlypreferred preferredembodiment, the process embodiment, the processgas gastemperature temperature is is 80 80 ° Cthe C and and the product temperature product temperatureisis40 40C. ° C.

Accordingtotothe According theinvention, invention, droplets droplets from from the the spray spraycomposition composition and and solid solid particlesare particles are brought into brought into contact contact with with one oneanother anotherininaaspouted spoutedbed. bed. Spouted Spouted bed bed is understood is understood to to mean mean that that thethe completely completely fluidized fluidized solid solid particles particles are inare in a closed a closed solids solids flow flow that is that is stable stable over time. over time. The Thespouted spoutedbed bed is is generated generated with with thethe help help of of thethe process process gasgas jet,jet, which which is is guidedinin aadefined guided definedmanner. manner. There There are three are three fluidization fluidization states states or zones or zones withinwithin the the spoutedbed. spouted bed.InInaafirst first zone or ejection zone or ejection zone, the solid zone, the solid particles particlesare are accelerated accelerated under under

the action the action of of the the process gasjet, process gas jet, which is guided which is in aa defined guided in defined manner, manner,the theparticles particlesinin this zone this movingininthe zone moving thedirection direction of of flow flow of of the the process gasjet. process gas jet. The processgas The process gasjet jetisis typically guided typically guidedvertically verticallyupwards. upwards. Accordingly, Accordingly, in the in the ejection ejection zone of zone of thebed the spouted spouted bed there is there is aa predominantly vertical upward predominantly vertical flow. In upward flow. In a a subsequent second subsequent second zone zone or or fountain fountain

zone, the zone, the particles particles change their direction change their direction of of flow. flow. There There is is predominantly predominantly aa cross crossflow. flow. Eventually Eventually the Eventually the the particles particles particles enter enter enter a third aa third third zonezone zone or or return or return return zone. zone. zone. There There There the the the particles particles particles then movethen then move move downwards downwards untilthey until theyfinally finally come backunder come back underthe theinfluence influenceofof the the process processgas gasjet, jet, which which

is guided is guided inina adefined defined manner, manner, and and are arecarried again again along carried along by it byfirst in the it in the zone.first zone. In the In the return zone, return zone,thethe particles particles typically typically move move underunder the influence the influence of gravity. of gravity.

8

Thespray The spray composition composition can can be be sprayed sprayed through two-fluid through two-fluid and multi-fluid and multi-fluid nozzles. Itnozzles. is also It is also possibletotoeffect possible effectthe thespraying spraying through through pressure pressure nozzles. nozzles. Alternatively, Alternatively, dropletization dropletization can can be carried be carried out outusing usingrotary rotaryatomizers, atomizers, jetjetcutters, cutters,ultrasonic ultrasonicdropletizers dropletizers andand other other

devicesknown devices known to the to the person person skilled skilled in thein the art. art.

According According to to thethe invention invention it is it is possible, possible, by spraying by spraying droplets droplets of a composition of a spray spray composition into into the process the process space space and and drying drying these these droplets droplets to form to formfrom nuclei nuclei from solid solid particles, particles, and theseand these are then are thenbrought brought into into contact contact withwith further further droplets droplets in order in order to particles to form form particles of the of the desired desired

size. As size. Asananalternative alternativeor or in in addition, addition, solid solid particles particles cancan be supplied be supplied from from the the outside outside into into the process. the For example, process. For example,excessively excessivelysmall smallparticles particlesremoved removed from from thethe process process cancan be be returned to the returned to the process spaceasasseed process space seedmaterial. material.Likewise, Likewise,excessively excessivelylarge largeparticles particlesor or agglomerates of agglomerates of particles particles removed from the removed from the process process can canbebecomminuted comminuted by any by any

comminutionunit comminution unitand andreturned returnedtotothe theprocess processspace space as as seed seed material. material.

Theparticles The particles formed formedbybythe themethod method according according to the to the invention invention are are removed removed from from the the processspace. process space.The The material material discharge discharge of of thethe finished finished product product from from thethe process process space space

or aa material or material transport transport into into aa process processspace space further further downstream downstream can place, can take take place, for for example, example, in in the the area area of the of the transition transition fromfrom the cross the cross flow toflow the to the downward downward flow flow of solids. of solids. Accordingtoto one According oneembodiment, embodiment,thethe particles particles discharged discharged from from the the process process space space are are not not classified. According classified. According to to another another embodiment, theparticles embodiment, the particlesdischarged dischargedfrom fromthe theprocess process spaceare space areclassified classified and removed and removed byby one one or or more more classifiers. classifiers.

Themethod The method according according to to the the inventioncan invention can be be carried carried out,for out, forexample, example,with withthe theaid aidofof aa device as device as described describedininDEDE103103 22 22 062062 A1. A1. The The content content of this of this application application is made is made the the subjectofofthe subject thepresent present application application by reference. by reference.

Themethod The method according according to to theinvention the inventionisispreferably preferably carried carried out out using a device using a as shown device as shown in the in accompanying the accompanying figure. figure. This This is explained is explained in detail in detail below. below.

Theprocess The processgasgas 10 (usually 10 (usually heated heated air)fed air) is is to feda to a supply supply air chamber air chamber 17 with 17 a with a rectangular cross rectangular cross section section 9 and 9 and delimiting delimiting side walls side walls 5. The 5. The process process gas 10 is gas 10 is distributed distributed

in the in the supply supply air airchamber 17and chamber 17 andenters entersthe theprocess process space space 8 via 8 via gapgap openings openings 1 in1the in the formofofgas form gasjets jets2.2.The The process process gas flow, gas flow, which which preferably preferably enters enters the gap 1 the gap 1 horizontally, horizontally,

is deflected is deflected by by the the deflecting deflecting part part3, 3,preferably preferablyupwards into the upwards into the process space8,8,and process space and flows into flows into the the apparatus as aa type apparatus as type of of free free jet. jet.Furthermore, Furthermore, the the apparatus cross-section apparatus cross-section

can optionally increase can optionally in the increase in the expansion zone14, expansion zone 14,sosothat thatthe thespeed speedofofthe theprocess process gas gas

flow decreases flow steadilytowards decreases steadily towardsthe thetop. top.The Thegas gas leaves leaves thethe apparatus apparatus as exhaust as exhaust gas gas 11 abovethe 11 above theexpansion expansion zone zone 14 the 14 via via exhaust the exhaust air part air part 19, into 19, into whichwhich a dedusting a dedusting

system(for system (forexample example filter filter cartridges cartridges or textile or textile filterelements) filter elements) can can optionally optionally be be integrated. integrated.

9 In In the the process process space space 88 there there is is aa large largenumber of particles number of particleswhich which are are carried carriedupwards by upwards by

the process the processgas gasjet. jet.Solid Solidparticles particles can canbebeintroduced introduced into into thethe process process space space at at the the beginningof beginning of the the process; process; however, however,the theprocess process can can also also be be started started by by generating generating solid solid

particles from particles from sprayed-in sprayed-in spray composition. spray composition.

In In the the upper upper area area of of the the process process space space 88 and andinin the the expansion expansionzone zone1414 located located above above it,it,

the gas the velocity decreases, gas velocity sothat decreases, so that the the upwardly upwardlyflowing flowingparticles particles emerge emergelaterally laterally from from the gas the gas jet jet 23 23 and fall back and fall back into intothe theprocess process space 8. The space 8. processspace The process space 8 isdelimited 8 is delimited in the in the lower lowerarea area by inclined by inclined side 29. side walls walls As a29. As of result a result of this this lateral lateral inclination, inclination, the the particles are particles areconveyed conveyed under under the action the action of gravity of gravity via thevia the zone return return zone 24 in the 24 in the direction direction of the of the gas inlet gap gas inlet gap 1, 1, where they are where they are then then carried carried along along again againby bythe theprocess processgas gas into into

the process the space8.8. process space

This mechanism This creates mechanism creates a very a very uniform uniform solidscirculation solids circulation 15 15 consisting consisting of of an an upward flow upward flow

anda areturn and return in in thethe direction direction of the of the process process gas As gas inlet. inlet. As a even a result, result, witheven very with small very small amounts amounts of of particles particles in the in the process process spacespace 8 in 8 in the thezone core core zone above theabove the part deflection deflection 3, part 3, thereisis aahigh there highparticle particledensity. density. In In this this area, area, one one or more or more spray nozzles spray nozzles 7 are 7 are arranged, arranged, whichspray which sprayupwards upwardsininthe thesame same directionasasthe direction theprocess process gas gas jetjetand andserve serve totointroduce introduce the spray the composition. spray composition.

Thehigh The highparticle particle loading loading in in thethe core core zonezone results results in very in very advantageous advantageous conditionsconditions for the for the heat and heat andmass masstransfer transferininthe the spray sprayzone zone22. 22.The Thespray spray composition composition rapidly rapidly loses loses liquid liquid

by evaporation. by evaporation.When When solid solid particlesthat particles thatare arealready alreadyininthe theprocess process space space comecome into into contact with contact with droplets droplets of ofthe thespray spraycomposition, composition, which which may havealready may have alreadylost lostsome someofof the the

liquid contained, liquid larger contained, larger particles particles andand aggregates aggregates of particles of particles are formed. are formed.

Theprocess The processgas gas can can discharge discharge some some of the of the particles particles as as well well as as fine fine materialand material and dusts dusts

fromthe from theprocess process space space 8 as 8 as exhaust exhaust air 20 air 20 containing containing solids. solids. The The filter filteroptionally system system optionally integrated in integrated in the the exhaust exhaust air airpart part19 19orordedusting dedustingsystems systems connected downstream connected downstream of of thethe

apparatuscan apparatus canbebeused usedtotoremove remove these these particles.InInthe particles. thecase caseofofan anintegrated integrateddedusting dedusting system25, system 25,compressed compressedair air pulses pulses 18 can 18 can be used, be used, for example, for example, in order in order to return to return the the retained particles retained particles as as separated solids 21 separated solids 21 to to the the process process space 8. space 8.

Compared Compared to fluidized to fluidized bed apparatus bed apparatus with integrated with integrated filter systems, filter systems, the return the return of dust is of dust is madeeasier made easierbyby the the factthat fact thatthe theupward upward process process gas gas flowflow is essentially is essentially localized localized andand

thus the thus the particles particles to tobe be returned returned can can safely safely sink sink outside outside of ofthe thegas gas jet. jet.This mechanism This mechanism

is additionally is additionally promoted promoted bybythe thesuction suction effectin inthethe effect vicinityofofthe vicinity thegas gas inletgap inlet gap 1. 1. Alternatively, particles Alternatively, particlesseparated separated from the exhaust from the exhaustair air can canbebereturned returnedtotothe theprocess process space8. space 8. For For this this purpose, purpose, various various types of feeds types of feeds 26 26 can be arranged can be arrangedinin the the lower lower region region of the of the inclined inclinedside sidewalls walls 29.29. DueDue to high to the the high speed speed of the process of the process gas jet ingas the jet in the vicinity vicinity

10

of the of gasinlet the gas inlet gap gap1,1,the thefine fineparticles particles are are drawn drawn in fed in and andtofed thetospray the spray zone zone 22, 22, where where they are they are wetted wetted with with spray spray composition compositionand andtake takepart partininthe the growth growthprocess. process.

Optionallybuilt-in Optionally built-inguide guide plates plates 16 16 stabilize stabilize the the particle particle circulation. circulation.

For continuousprocess For continuous process management, management, the apparatus the apparatus can optionally can optionally be equipped be equipped with with different entry different entry systems 13for systems 13 for solids. solids. In In this thisway, way, for for example, particles which example, particles canbebe which can

obtained by obtained bycomminuting, comminuting,forfor example, example, (too(too large) large) granules granules and and / or /which or which consist consist of of granules that granules that are are too too small small can canbebefed fedinto into the the process. process.These These particlesthen particles thenserve serve as as

granulationnuclei granulation nuclei or or as as a starter a starter fillingtotoshorten filling shorten the the start-up start-up time. time. In addition, In addition, additives additives

whichare which are to to be be embedded embedded in in the the granules granules cancan be be fedfed in in solidform solid forminto intothe theprocess. process.

Furthermore, theapparatus Furthermore, the apparatus can can be be provided provided withwith discharge discharge elements elements 4 in order 4 in order to be to be

able to able to remove removeparticles particlesfrom fromthethe process process space space 8. This 8. This can can be be done, done, for example, for example,

throughanan through overflow overflow or through or through a volumetric a volumetric discharge discharge element element (eg (egvalve) a rotary a rotary valve) or also or also througha agravity through gravity sifter(eg(eg sifter a zigzag a zigzag sifter sifter charged charged with sifting with sifting gas orgas or a pipe a riser risersifter). pipe sifter).

Mechanical Mechanical units units 27 can 27 can optionally optionally be attached be attached to the inclined to the inclined walls in walls in the space the process process space 8, but 8, but preferably in the preferably in the area of the area of the return return zone zone24, 24,inin order ordertoto produce produce sufficientfine sufficient fine material by material by comminution comminution asasnuclei nucleifor for the the granulate formation process. granulate formation process.Furthermore, Furthermore,the the return zone return zone2424can can optionallybebe optionally used used for for positioning positioning heaters heaters or other or other heat heat transfer transfer

devices 28. devices 28. For For example, example,the theapparatus apparatus wallcan wall can be be double-walled double-walled in order in order to to use use it,it,for for example, example, forfor heating heating or cooling or cooling the walls the walls using using liquid liquid or gaseous or gaseous heatmedia. heat transfer transfer In media. In this way, this way, optimal optimal surface surface temperatures canbebeset. temperatures can set.

In In the the process space8 8ororinin the process space the overlying overlying apparatus apparatusparts, parts, the the expansion expansionzone zone 14 14 andand

the exhaust the exhaustair air part part 19, 19, spray spray nozzles nozzles6 6can can optionallybebe optionally arranged, arranged, which which preferably preferably

spray downwards spray downwardsbut but alsoalso partially partially upwards. upwards. Here, Here, too,too, the the liquid liquid formulation formulation can can be be injected in injected in order order to to generate generate granulation nuclei in granulation nuclei in the the apparatus, apparatus, for for example byspray example by spray drying// spray drying spraysolidification. solidification.Alternatively, Alternatively,additives additives or or other other components components can be can be sprayed sprayed in in in in liquid liquidform form via via some of the some of the spray spray devices devices6 6and and 7 and 7 and thusthus embedded embedded

homogeneously homogeneously in in thethe granulate granulate structure. structure. When When the the spray spray nozzles nozzles 7 pass 7 pass through through the the temperature-loaded temperature-loaded supply supply airair chamber chamber 17, 17, the the liquid-carrying liquid-carrying parts parts cancan optionally optionally be be provided with provided with insulation insulation or or various various cooling coolingoror heating heatingsystems systems12 12 in order in order to prevent to prevent

damage damage toto theliquid the liquid formulation. formulation.

An advantage An advantageof of thethe process process according according to invention to the the invention is very is the the very simple simple structure, structure,

whichcombines which combines high high operational operational reliabilityand reliability andinsensitivity insensitivity to to malfunctions malfunctionswith withvery very goodcleaning good cleaningoptions. options.This Thiscreates creates improved improved production production conditions, conditions, particularly particularly withwith

regard to regard to pharmaceutical andhygiene pharmaceutical and hygiene requirements requirements when when changing changing products. products.

11

Anotheradvantage Another advantageis isthat thatthe theactive active ingredient ingredient used doesnot used does notneed needtotobebeground ground before before

further processing. further processing. After After adding adding tableting tableting excipients, excipients, further processing further processing into tabletsinto is tablets is possible. possible.

Theprocess The processaccording according to to the the inventionallows invention allows the the production production of of granules granules in in high high yield. yield.

Thereisispractically There practicallynono loss loss of active of active ingredient, ingredient, sincesince finelyfinely divided divided material material can can be fed be fed backinto back intothe theprocess process or, or, in the in the casecase of internal of internal classification, classification, is notiseven not discharged. even discharged.

Thepresent The presentinvention inventionalso alsorelates relates to to the the granules granules produced producedaccording according to to the the invention. invention.

Thegranules The granulesare areobtained obtainedbyby the the method method according according to the to the invention invention and and have have a d50 d ofaofd 50 of 50 to 50 to 1200 μm,for 1200 um, µm, for example examplefrom from 100 100 to to 600 600 µm,μm, um, preferably preferably from from 150150 to 500 to 500 µm. μm. um.

In In addition to or addition to or independently independently thereof, thereof, the the granules granules have ahave bulk a bulk density density of 0.400of to0.400 0.900 to 0.900

g/ml, preferably g/ml, preferablyofof0.500 0.500 to 0.600 to 0.600 g/ml.g/ml.

Theproduct The product according according toinvention to the the invention is flowable. is flowable.

Theproduct The productaccording according to to thethe invention invention hashas a high a high stability. stability. In In particular,there particular, thereisisnono aggregationor aggregation or clumping clumpingduring duringstorage. storage.

Granulesasasobtained Granules obtained above above can be can also also be further further processed processed into controlled-release into controlled-release

dosage dosage forms. forms. SuchSuch formsforms of administration of administration include,include, in particular, in particular, forms offorms of administration administration

whichonly which only release release the the active active ingredient ingredient in deeper in deeper intestinal intestinal sections, sections, such such as the as ileum the ileum or colon. or colon. According Accordingtotoone oneembodiment, embodiment, granulate granulate particles particles are are provided provided with with one one or or morefunctional more functional coatings coatings to control to control the release the release of active of active ingredient. ingredient.

Suitably selected Suitably selected coatings coatings only only dissolve dissolve in the in the part distal distal of part of the the small small intestine intestine (ileum) (ileum) and in and in the the subsequent colon.They subsequent colon. Theycontrol controlthe therelease releaseofof active active ingredient ingredient in in such such a a way way

that at that at least least 60%, preferably at 60%, preferably at least least 70% and 70% and ininparticular particularatat least least 80% 80%ofofthe theactive active ingredientare ingredient arereleased released in the in the ileum ileum and colon. and colon.

Suchcoatings Such coatingscan canbebeapplied, applied,for forexample, example,with withthe theaid aidof of aa Wurster Wurstermethod. method.

Suitable coating Suitable coating materials materials are are polymer compositions,inin particular polymer compositions, particular polymer compositions polymer compositions

whichlead which lead to to enteric enteric coatings coatings which which dissolve dissolve at at pH pH values above6.5, values above 6.5, such suchas asabove above6.8 6.8 andininparticular and particularabove above7.0.7.0.

Polymers obtained Polymers obtained by by polymerizing polymerizing acrylic acrylic acid, acid, methacrylic methacrylic acid acid andand their their esters esters are are

suitable. suitable.

Preferred polymers are Preferred polymers aremethacrylic methacrylic acid-methyl acid-methylmethacrylate methacrylatecopolymers copolymers (1:2), (1:2),

commerciallyavailable commercially availableasasEudragit® Eudragit®S S 100 100 (powder) (powder) and and as Eudragit® as Eudragit® S (organic S 12.5 12.5 (organic solution), as solution), as well well as as poly poly (methyl acrylate-co-methylmethacrylate-co-methacrylic (methyl acrylate-co-methylmethacrylate-co-methacrylic acid) acid)

7: 3: 7: 3: 1, 1,commercially commercially available available as as Eudragit® FS3030DD(aqueous Eudragit® FS (aqueous dispersion). dispersion).

12

Thesepolymers These polymers can can be be used used alone alone or in or in combination combination with with other other polymers, polymers, such such as other as other

Eudragit® types, Eudragit® types, in order in order to regulate to regulate the desired the desired releaserelease behavior. behavior.

Customary Customary excipientsand excipients and additivescan additives can be be mixed mixed with with thethe polymers. polymers.

Asananalternative As alternativetotocoating coating granulate granulate particles, particles, controlled-release controlled-release dosage dosage forms canforms also can also be provided be providedby byprocessing processinggranulate granulate particlesobtained particles obtainedbybythe theprocess process according according to to thethe

inventioninto invention intotablets tabletsor or fillingthem filling them into into capsules, capsules, whichwhich are are then then provided provided with with one or one or morecoatings. more coatings.The Theabove above information information applies applies toto thecoatings. the coatings.

Release fromthe Release from thecoated coatedtablets tabletsor or capsules capsulestakes takesplace placeinin such suchaaway waythat thatat at least least 60%, 60%,

preferablyatatleast preferably least70% 70% and and in particular in particular at least at least 80% 80% of the of the active active ingredient ingredient is released is released

in the in ileumand the ileum and colon. colon.

Investigation methods Investigation methods

Theparticle The particle analyses are carried analyses are carried out out with with the the optical opticalimage image evaluation evaluation system Camsizer system Camsizer

XT(Retsch). XT (Retsch).The TheCAMSIZER CAMSIZER XTthe XT uses uses the principle principle of digital of digital image image processing. processing. The The dispersedparticle dispersed particle stream streampasses passestwotwo LED LED stroboscopic stroboscopic light light sources. sources. The shadows The shadows

projected by projected by the the particles particles are are recorded by two recorded by twodigital digital cameras. Theparticle cameras. The particle diameter diameterisis determinedasasthe determined theshortest shortestchord chordofofthe themeasured measuredsetset of of maximum maximum chords chords of a particle of a particle

projection. projection.

A particle A particle population population can can be characterized by be characterized by aa cumulative cumulativevalue valueQ3(x), Q3(x),which whichindicates indicates the percentage the percentage volume volume fraction fraction of particles of particles smallersmaller than x relative than X relative to the to the total totalofvolume volume of the particles. the particles.The The value value dd50 denotes denotes d50denotes the the the value Xx value value atat X at which which which Q3(x) isis Q3(x) Q3(x) is 50%. 50%. 50%.

Themoisture The moisturecontent contentofofthe theproduct productisisdetermined determined with with thethe Sartorius Sartorius MA MA 100 100 moisture moisture

analyzer (halogen analyzer (halogenlamp; lamp;105 105°C°C andand automatic automatic switch-off). switch-off). TheThe moisture moisture content content of the of the

granulesaccording granules according to the to the invention invention is typically is typically less 1% less than than 1% by by weight. weight.

For the optical For the optical assessment of the assessment of the samples, samples, recordings recordings are are made madewith withthe theAXIO AXIO microscope(Zeiss). microscope (Zeiss).

To characterize To characterize the the material, material,the thetest samples test samplesare aremeasured measured with with the the D2 Phaser D2 Phaser

(Brucker)X-ray (Brucker) X-ray diffractometer. diffractometer.

Bulk volume Bulk volume// bulk bulk density density are are measured measured ininaameasuringcylinder. measuringcylinder.The The sample sample is is carefully carefully

pouredinto poured into the the measuring cylinder. It measuring cylinder. It must must not not be be compacted (knocked compacted (knocked or or bumped). bumped).

After determining After the bulk determining the bulkvolume volume / bulkdensity / bulk density in in themeasuring the measuring cylinder, cylinder, thethe same same

sampleisis mechanically sample mechanicallytamped tamped in the in the cylinder cylinder (tamping (tamping volumeter volumeter ERWEKA ERWEKA SVM 20) SVM 20) andthe and thevolume volume is read is read off again. off again. This This is continued is continued until practically until practically no further no further changes changes in in volumeare volume areobserved. observed.

13

Bulk andtamped Bulk and tamped density density are are calculated calculated from from thethe measured measured values values of mass of mass andor and bulk bulk or tamped volume. tamped volume.

Theangle The angleofofrepose reposeisisthe theangle angleofofflow flowinclination inclination that that results resultswhen a product when a product flowing flowing freely from freely from aa funnel funnelforms forms aa cone cone on on a a surface. surface. The The determination is made determination is with aa RTG01 made with RTG01 trickle tester. trickle tester.

14

Examples Examples

Theinvention The inventionisis illustrated illustrated by meansofofspecific by means specificapplication applicationexamples, examples, without without being being

restricted in restricted in any anyway. way.

Example Example 11-- Preparation Preparation of of Spray Spray Compositions Compositions

Themetformin The metforminhydrochloride hydrochloridetotobebeprocessed processedwaswas completely completely clumped clumped into into a large a large lump. lump.

Thelarge The large lump lumpofofactive active ingredient ingredient first first had had to tobe bebroken broken into into small small pieces, pieces, which which were were

thencrushed then crushed further further withwith the the help help of a of a rotor-stator rotor-stator mill. mill.

A suspension A suspensionwith witha adry drymatter mattercontent contentofof50% 50%inindistilled distilled water water was preparedfrom was prepared fromthis. this. Thesuspension The suspensionwaswas stirred stirred with with a paddle a paddle stirrer stirrer andand thenthen passed passed through through a 500 a µm500 um μm sieve in sieve in order order to to prevent prevent nozzle nozzle blockages. It was blockages. It foundthat was found that coarser coarser components components were were

still present still presentinin thethesuspension. suspension.The The suspension wasstirred suspension was stirredagain againusing usingananUltra UltraTurrax Turrax T-50 (IKA) T-50 (IKA) for for 10 10 minutes minutesatat10,000 10,000rpm. rpm. Allsuspensions All suspensionsof of thethe following following experiments experiments

wereprepared were preparedininthe thesame same way. way.

In In a further experiment, a further experiment, aasolution solutionofofmetformin metformin hydrochloride hydrochloride was was prepared. prepared. It was It was

possibletotoobtain possible obtain a solution a solution in water in water with with a drya matter dry matter contentcontent of 28%. of The28%. Ultra The Ultra Turrax Turrax also had also hadtotobebe used used for for this. this.

Example Example 2 2 - -Preparation Preparationof of a a metformin metformin hydrochloride hydrochloride product product without without the addition the addition

of excipients of excipients

Thegranulation The granulation tests tests were were carried carried out continuously out continuously in a laboratory in a laboratory system system with with a spouted a spouted bedinsert. bed insert.

Thespray The spraycomposition compositionwas was atomized atomized with with a bottom a bottom spray spray nozzle nozzle (two-substance (two-substance nozzle; nozzle;

nozzle air nozzle air temperature not heated). temperature not heated).

A metformin A metforminhydrochloride hydrochloride solution solution in water in water withwith a matter a dry dry matter content content of 28%ofwas 28% was sprayedinto sprayed into the the apparatus. apparatus.

Thespray The spraycomposition composition waswas conveyed conveyed from from the the storage storage container container (5 l container; (5 I container; not not heated)totothe heated) thenozzle nozzle using using a peristaltic a peristaltic pump.pump.

Filters Filterswere were arranged abovethe arranged above thespouted spouted bed. bed. They They were were cleaned cleaned regularly regularly by blasts by blasts of of

compressed compressed airairsosothat thatthe thedust dustremained remainedininthe theprocess processspace. space.

Theprocess The processair airwas wasconveyed conveyed through through the speed-controlled the speed-controlled exhaust exhaust fan. fan. An An electrical electrical

heatingregister heating registerwaswas usedused to heat to heat the the air. air.

15

Theproduct The productdischarge discharge was was regulated regulated by means by means of flow of air air flow in the in the zigzag zigzag sifter, sifter, so so that, that,

under stable under stable operating operatingconditions, conditions,the thesame same amount amount of dry of dry matter matter was discharged was discharged as as dust-free granulate dust-free granulate as wassupplied as was suppliedwith with the the spray spraycomposition. composition.

Thefine The fine dust dust from from the the classifier classifier was was conveyed backinto conveyed back intothe the process processchamber. chamber.

Accordingtotothe According themethod method described, described, active active ingredient ingredient pelletsconsisting pellets consistingofof100% 100% active active

ingredient ingredient could ingredient could couldbe be obtained obtained be from fromfrom obtained thesolution solution. the solution. the

Theprocess The processwas was very very stable. stable.

First First of of all, all,small small particles wereproduced particles were produced (sample (sample A; d50 A; d50 =um). = 123.2 123.2 µm). µm).

Thespray The spraypressure pressurewas was then then lowered lowered andand thethe spray spray rate rate increased increased to to encourage encourage particle particle

growth. Larger growth. Larger particles particles could could then then be produced(sample be produced (sampleB;B; d d d50 = 50= =300.9 300.9 300.9 µm). um). µm).

Example Example 3 PVP 3 - - PVP andand Particle Particle SizeSize

For this example, For this example, aa suspension suspensionofofmetformin metformin hydrochloride hydrochloride in in water water with with 5% 5% by weight by weight

of PVP of KollidonK-30 PVP Kollidon K-30(based (based on on thethe drydry matter) matter) was was prepared. prepared. The suspension The suspension had a had a dry matter dry matter content content of of 51.3%. Theprocess 51.3%. The processwas was startedwith started withthe theremainder remainderofofthe theprevious previous experiment. experiment.

A 2.0 A 2.0 mm mmnozzle nozzlewas was used. used. TheThe suspension suspension was stirred was stirred whilewhile spraying. spraying.

Theproduct The productdischarged discharged from from the the process process area area hadhadd aof a d50 dof of 197.6 197.6 197.6 50 um.μm. µm.

Thespray The spraypressure pressurewas was then then lowered lowered andand thethe spray spray rate rate increased increased to to encourage encourage particle particle

growth. The growth. Theproduct productdischarged discharged after after thethe layer layer mass mass had had been been replaced replaced hadofofa had a d50 d5 d50 of 423.6 μm. 423.6 um. µm.

Theparticle The particle size size distribution distribution of of the the product is shown product is shown ininFig. Fig.2.2.The Themicrograph micrograph of aof a sampleisis shown sample shownininFig. Fig. 3. 3. The productparticles The product particles obtained representaggregates obtained represent aggregatesofoffirmly firmly connectedspheres. connected spheres.

It Itwas was possible to produce possible to different particle produce different particlesizes sizeswith withaaPVP content of PVP content of 5% 5%ininthe theend end product. product.

16

Example 44-– Throughput Example Throughput

In In this this test, test,the theprocess process was to be was to be further further optimized. For this optimized. For this reason, anattempt reason, an attemptwas was madetotoconcentrate made concentratethe thesuspension suspensionof of metformin metformin hydrochloride hydrochloride and and PVP PVP in water in water more more

highly. AA suspension highly. with aa dry suspension with dry matter matter content of 69.4% content of wasobtained. 69.4% was obtained.Based Basedon on thethe drydry

matter content, there matter content, there was again5% was again 5%PVP PVP in in thethe suspension. suspension.

Despite thehigh Despite the highviscosity, viscosity, it it was possibletotospray was possible spraythethe suspension. suspension. Because Because of theof the

smaller amount smaller amountofofwater waterthat that had hadtoto be beevaporated, evaporated,a alarge largeincrease increaseininthroughput throughputcould could be achieved be achieved(1.3 (1.3kg/h kg/hin in example example 3;3;2.9 2.9kg/h kg/hin in the the present example). present example).

First, First,aasmall smallparticle particlesize was size wasproduced again (d50 produced again (d50= = (d = 186.8 186.8 186.8 µm). um). µm). Larger Larger Larger particles particles particles were were were

then produced then produced(d50 (d(d=50==475.3 475.3 475.3 µm). um). µm). The The The process process process ended ended ended without without without nozzle nozzle nozzle blockages blockages blockages oror or other other other

problems. problems.

Example 5 -Variation Example 5 - Variationofof thebinder the binder content content

For this test, For this test,the thePVP PVP content content was reducedfrom was reduced from5%5% to to 2.5% 2.5% (based (based on the on the dry dry matter). matter).

Theconcentration The concentrationofofthe the suspension suspensionwas was maintained maintained (68.8%). (68.8%). After After the the layer layer mass mass had had beenexchanged, been exchanged, firstsmall first smallparticles (d50= ==184.7 particles (d50 (d 184.7 184.7 μm) um) µm) and and and then then then coarser coarser coarser particles particles particles (d = 50 == (d(d50

269.2 um) 269.2 μm)were µm) wereproduced. produced.

A suspension A suspensionwas was prepared prepared again again forfor a furthertest a further test (dry (dry matter matter content 70.2%). This content 70.2%). This time time only 1% only PVP 1% PVP (based (based on on thethe drydry matter) matter) waswas added. added. Here, Here, too, too, a small a small particle particle size size waswas

initially initially initially produced produced produced (d(d 50== (d50 165.3 =165.3 165.3 µm). um). Later Later µm). larger larger Later particles particles larger (d50 (d particles = (d == 230.5 230.5 50 µm) um) were 230.5 were produced. µm)produced. were produced.

So again So again particles particles of of different different sizes sizes can can be produced. be produced.

Example 6 -Flowability Example 6 - Flowability

Various parameters Various parameters were were determined determined that allow that allow conclusions conclusions to beabout to be drawn drawntheabout the flowability of flowability of products. products.

Thepure The pureactive active ingredient ingredient was wasslightly slightly deagglomerated forthe deagglomerated for the measurement measurement so that so that thethe

investigationcould investigation could take take place place at all. at all.

TheHausner The Hausner factorwas factor was determined determined as the as the ratio ratio of of tamped tamped density density to bulk to bulk density. density. For For

values close values close to to 1, 1, good dosingaccuracy good dosing accuracy can can be be expected; expected; for for values values wellwell above above 1, the 1, the

dosing accuracy dosing accuracycancan depend depend on vibrations. on vibrations. In present In the the present case, case, a a reduction reduction in the in the Hausner factorfor Hausner factor for the the samples samples according according to to thethe invention invention in in comparison comparison withwith the the raw raw

material material shows animprovement shows an improvement in the in the metering metering accuracy. accuracy.

17

TheCarr The Carrindex indexwas wasdetermined determined using using thethe formula formula 100100 x (bulk X (bulk volume volume - tamped - tamped volume) volume)

// bulk bulk volume. SmallerCarr volume. Smaller Carrindices indices show show better better flowflow behavior. behavior. A value A value less less than than 15 15 indicatesa afree-flowing indicates free-flowing product. product.

A small A small angle angle of of repose reposeshows showsgood good flow flow behavior. behavior.

Table 11 Table

Angle Angle Bulk Bulk Bulk Bulk Tamped Tamped Tamped Tamped Hausner Hausner Carr Carr of of Sample Sample volume volume Weight density Weight density volume volume density factor density factor index repose index repose ml ml g g g/ml g/ml ml ml g/ml g/ml °O o

95%Metf. 95% Metf. / 5% / 5% PVP PVP 174 174 98.9 98.9 0.568 0.568 163 163 0.607 0.607 1.067 1.067 6.322 6.22 6.322 6.22 97.5 97.5 %% Metf. Metf. // 2.5 2.5 % PVP % PVP 168 168 100 100 0.595 0.595 156 156 0.641 0.641 1.077 1.077 7.143 6.11 7.143 6.11

Example 7 -Stability Example 7 - Stability

Samplesaccording Samples according to to the the invention invention were were stored stored in in sealed sealed plastic plastic bags bags forfor 3 months 3 months at at roomtemperature. room temperature.The The good good flowabilitywas flowability was retained. retained.

Example 8 -Manufacture Example 8 - Manufacture of tablets of tablets

Tablets were Tablets weremade made using using metformin metformin hydrochloride hydrochloride products products as obtained as obtained in some in some of theof the precedingexamples. preceding examples.

Thecomposition The compositionand and properties properties ofofthe themetformin metformin hydrochloride hydrochloride products products used used are are given given

in Table in Table 2 2 below: below:

18

Table 22 Table

Product Product Product PVP content PVP content d50 d50 Bulk density Bulk density Residual Residual

d moisture moisture

P1 P1 5% 5 % 197.6 197.6 µm um µm n.d. n.d. 0.71 % 0.71 % 5% P2 P2 5% 5 % 423.6 µm 423.6 um µm 0.510 g/ml 0.510 g/ml 0.69 % 0.69 % 5% P3 P3 2.5 % 2.5 % 184.7 184.7 µm um µm 0.582 g/ml 0.582 g/ml 0.29 % 0.29 %

P4 P4 2.5 2.5 % % 269.2 µm 269.2 um µm 0.529 g/ml 0.529 g/ml 0.38 0.38 % %

P5 P5 - - 123.2 123.2 µm um µm 0.851 g/ml 0.851 g/ml 0.23 0.23 % %

P6 P6 - - 300.9 300.9 µm um µm n.d. n.d. 1.06 1.06 % %

In In order order to to produce tableting mixtures, produce tableting mixtures, 1,000 1,000parts partsbybyweight weightmetformin metformin hydrochloride hydrochloride

product was product wasmixed mixed with3 3parts with partsbyby weight weight magnesium magnesium stearate stearate as a as a release release agent agent and and ®) 31 parts 31 partsbybyweight weight of of croscarmellose croscarmellose sodium sodium (AcDiSol (AcDiSol R) as disintegrating ®) as disintegrating agent, agent, respectively. respectively.

A tablet A tablet press from Fette press from Fette (102i) (102i) with with aa punch punchdiameter diameterofof approx. approx. 10 10 mm mm was used was used to to producebiconvex produce biconvextablets. tablets. The Thefilling filling depth depthwas was 99 mm. A speed mm. A speedofof 10,000 10,000tablets tablets per per hour hour was used. was used.

Further Further parameters aregiven parameters are givenininTable Table33below. below.

Table 33 Table

No. No. Product Product Product Web Web Pre- Pre- Webheight Web height Main Main Dimens Dimens height height pressing pressing pressing pressing ions ions mm mm force force mm force force mg mm mg kN kN kN kN

T1.1 T1.1 P1 P1 4.7 4.7 3 3 4.2 4.2 6.8 6.8 382 382 382

T1.2 T1.2 P1 P1 5.2 5.2 1.4 1.4 4.7 4.7 3 3 381 381

T1.3 T1.3 P1 P1 4.3 4.3 4 4 3.8 3.8 9.4 9.4 372 372

T2.1 T2.1 P2 P2 4.7 4.7 1.4 1.4 4.2 4.2 3 3 346

19

No. No. No. Product Product Web Web Pre- Pre- Webheight Web height Main Main Dimens Dimens height height pressing pressing pressing pressing ions ions mm mm force force mm force force mg mm mg kN kN kN kN

T2.2 T2.2 P2 P2 4 4 2.5 2.5 3.5 3.5 6.7 6.7 328 328

T2.3 T2.3 P2 P2 3.5 3.5 4.6 4.6 3.2 3.2 9.3 9.3 320 320

T3.1 T3.1 P3 P3 4.2 4.2 4 4 3.75 3.75 9.1 9.1 370 370

T3.2 T3.2 P3 P3 4.3 4.3 3 3 3.85 3.85 7 7 376 376

T3.3 T3.3 P3 P3 4.7 4.7 1.6 1.6 4.3 4.3 3.1 3.1 359 359

T4.1 T4.1 P4 P4 4.9 4.9 1.5 1.5 4.5 4.5 3 3 373 373

T4.2 T4.2 P4 P4 4 4 4 4 3.5 3.5 9 9 350 350

T4.3 T4.3 P4 P4 3.9 3.9 2.7 2.7 3.5 3.5 6.2 6.2 332 332

T5.1 T5.1 P5 P5 5.5 5.5 3.3 3.3 5 5 7.2 7.2 453 453

T5.2 T5.2 P5 P5 5.2 5.2 4.4 4.4 4.7 4.7 10.5 10.5 445 445

T6.1 T6.1 P6 P6 4.9 4.9 3.8 3.8 4.4 4.4 11 11 442 442

T6.2 T6.2 P6 P6 5 5 1.3 1.3 4.5 4.5 4.7 4.7 414 414

In In all allcases cases tablets tabletswhich whichhad had acceptable disintegration times acceptable disintegration times could could be be obtained. obtained.

Example Example 9 Preparation 9 - - Preparation of of Coated Coated Granular Granular Particles Particles

Coatedgranules Coated granulesareare made made fromfrom a metformin a metformin hydrochloride hydrochloride granulate. granulate. The purpose The purpose of of the coating the coatingisistotoensure ensure thatthat the the active active ingredient ingredient is released is released primarily primarily in the in the ileum andileum and colon. colon. colon.

Formulation of an Formulation of an exemplary exemplarycoating coatingsuspension: suspension:

EUDRAGIT® EUDRAGIT® FS FS 30 30 D (availablefrom D (available fromEvonik Evonik Roehm RoehmGmbH, GmbH, Darmstadt, Darmstadt, DE) DE) 2000 2000 g g

Talc (available Talc (available from from Merck KGaA, Merck KGaA, Darmstadt, Darmstadt, DE)DE) 300 gg 300

Triethyl citrate Triethyl citrate (TEC) (TEC)(available (available from from Vertellus Vertellus Inc.,Inc., Greensboro, Greensboro, USA) USA) 37.5 gg 37.5

Water(demineralized) Water (demineralized) 2350 gg

20

To produce To produce the the coating coating suspension, suspension, EUDRAGIT® EUDRAGIT® FS FS 30 30 D, D, talcand talc andTEC TEC areare mixed mixed

using aa paddle using paddlestirrer stirrer (IKA (IKA GmbH & Co. GmbH & Co. KG, KG, Staufen, Staufen, DE). DE). The suspension The suspension is passed is passed

through aa 0.1 through 0.1 mm mmsieve. sieve.

Thesuspension The suspension has has a solidscontent a solids content ofof20.0% 20.0%andand a polymer a polymer content content of 12.8%. of 12.8%.

Thesuspension The suspensionis isapplied appliedtotometformin metformin hydrochloride hydrochloride granules granules (d =(d= (d50 =µm) 50350 350 350 um) μm) ausing using using a a fluidized bed fluidized process.For bed process. Forthis this purpose, purpose,a aGlatt GlattGPCG GPCG 1 fluidized 1 fluidized bed system bed system (Glatt (Glatt

GmbH, GmbH, Binzen, Binzen, DE) DE) with with a 1.2 a 1.2 mmmm nozzle nozzle (top(top spray) spray) and and an atomizing an atomizing air pressure air pressure of 2of 2 bar is bar is used. used. Further processparameters Further process parametersareare a spray a spray rate rate of of 7-10 7-10 g/min/kg, g/min/kg, an an inlet inlet airair temperatureofof38-40 temperature 38-40oO °CCand andananoutlet outlettemperature temperatureofof26-30 26-30 °C. °C.

Thesuspension The suspensionisissprayed sprayedininuntil until 30.0% 30.0%bybyweight weightofofpolymer, polymer,based based on on thethe metformin metformin

hydrochloride granulate hydrochloride granulateused, used,has hasbeen been applied. applied.

Theend The endproduct productisisthen thendried driedin in the the unit. unit. To To prevent prevent agglomeration, 0.5%Aerosil® agglomeration, 0.5% Aerosil® 200 200

(pyrogenic silicondioxide) (pyrogenic silicon dioxide) is is added added before before drying. drying.

21

Reference symbols Reference symbols

1 1 Gap(s) Gap(s)

2 Gas 2 Gasjet(s) jet(s)

3 Deflection 3 Deflectionpart part

4 Discharge 4 element Discharge element

5 Side 5 Sidewall wall

6 Spray 6 nozzle(s) spraying Spray nozzle(s) sprayingin in any anydirection direction

7 Spray 7 Spraynozzle(s) nozzle(s) spraying sprayingupwards upwards

8 Process 8 Process space space

9 Cross-section 9 of aa process Cross-section of processstep step

10 Processgas 10 Process gas

11 Exhaustgas 11 Exhaust gas

12 Insulation with 12 Insulation with cooling cooling or orheating heatingsystem system

13 13 Feed Feed system system

14 14 Expansion Expansion zone zone

15 Solidscirculation 15 Solids circulation

16 Baffle(s) 16 Baffle (s)

17 Supplyair 17 Supply air chamber chamber

18 Compressed 18 Compressed airair pulses pulses

19 Exhaustsection 19 Exhaust section

20 Solids-laden 20 Solids-laden exhaust exhaustair air

21 Separated 21 Separatedand and recycled recycled solidmatter solid matter

22 Spray 22 Spray zone zone

23Particle 23 Particleexit exitfrom fromthethe gasgas jet jet

24 Return 24 Returnzone zone

25 Dedusting 25 Dedustingsystem system

26 Feeders 26 Feeders

22 27 Mechanical 27 Mechanicalaggregates aggregatesforfor sizereduction size reduction

28 Heat 28 Heattransfer transfer devices devices

29 Side 29 Side wall wall

23 10 Jun 2025 2020272151 10 Jun 2025

Theclaims The claimsdefining defining the the invention invention areare as follows: as follows:

1. 1. A process A process for for thethe continuous continuous production production of active of an an active ingredient ingredient granulate, granulate,

comprising the following comprising the following steps: steps: (a) (a) preparing preparing a a spray spray composition bydissolving composition by dissolving or or dispersing dispersing an an active active ingredient ingredient and optionallyoneone and optionally or or more more excipients excipients in a liquid; in a liquid; 2020272151

(b) (b) providing solidparticles providing solid particlesinina aprocess process space; space;

(c) (c) introducing droplets introducing droplets of of thethe spray spray composition composition into aninto an injection injection zone of zone the of the process spaceininwhich process space whichthe theliquid liquid evaporates; evaporates; (d) (d) repeated guiding repeated guiding of the of the solid solid particles particles pastpast the sprayed the sprayed droplets droplets in the process in the process

space with space with the the aidaid of of a process a process gas so gas jet, jet,that so at that at least least a portion a portion of the of the droplets, droplets,

which may which mayhave have already already lostpart lost partofofthe the liquid liquid contained, contained, comes into contact comes into contact with with solid particles and solid particles andlarger larger solid solid particles particles areare formed formed through through agglomeration; agglomeration;

(e) (e) removing the active removing the active ingredient ingredient granulate granulate from from the the process spaceininthe process space the form formof of solid particles, solid particles,

whereinthe wherein the active active ingredient ingredient comprises metforminororananacid comprises metformin acidaddition additionsalt salt of of metformin, in particular metformin, in particularmetformin metformin hydrochloride. hydrochloride.

2. 2. TheThe process process according according to claim to claim 1, wherein 1, wherein the active the active ingredient ingredient is metformin is metformin

hydrochloride. hydrochloride.

3. 3. TheThe process process according according to claim to claim 1 or 12, orwherein 2, wherein the liquid the liquid is is water. water.

4. TheThe 4. process process according according to one to any anyof one ofpreceding the the preceding claims, claims, wherein wherein the spray the spray

composition additionally composition additionally contains contains a binder. a binder.

5. 5. TheThe process process according according to one to any anyof one ofpreceding the the preceding claims, claims, wherein wherein the the dry dry matter content of matter content of the the spray spray composition is at composition is at least least25% by weight. 25% by weight.

6. 6. TheThe process process according according to claim to claim 5, wherein 5, wherein the proportion the proportion of the of the active active ingredient ingredient

in in the dry matter the dry mattercontent content is is at at least least 70%70% by weight. by weight.

7. 7. TheThe process process according according to one to any anyof one ofpreceding the the preceding claims, claims, wherein wherein the spray the spray

composition is aa suspension. composition is suspension.

24 10 Jun 2025 2020272151 10 Jun 2025

8. 8. TheThe process process according according to one to any anyof one ofpreceding the the preceding claims, claims, wherein wherein the provision the provision

of of particles particlesaccording according to tostep step(b) (b)takes takesplace placeby byspraying sprayingthe thespray spraycomposition composition

into into the the empty empty process spaceand process space and evaporating evaporating thethe liquidininthe liquid the process processspace. space.

9. 9. TheThe process process according according to one to any anyof one ofpreceding the the preceding claims, claims, wherein wherein in step in step (e) (e) particles particles which which have reacheda apredetermined have reached predetermined size size areare removed. removed. 2020272151

10. 10. The The process process according according to any to any one one of claims of claims 1 to1 8, to wherein 8, wherein solid solid particleswhich particles which have not reached have not reacheda aspecified specifiedsize sizeare are returned returnedto to the the process processspace. space.

11. 11. The The process process according according to any to any one one of the of the preceding preceding claims, claims, wherein wherein excessively excessively

large large particles particlesare arereturned returnedto tothe theprocess processspace space after aftercomminution. comminution.

12. 12. The The process process according according to any to any one one of the of the preceding preceding claims, claims, in which in which the the particle particle

size size of of the the particles particlesremoved, removed, expressed asthe expressed as the dd50 value, value, isis100 100toto600 600µm. µm.

13. 13. AnAn active active ingredientgranulate, ingredient granulate,the theparticle particle size, size, expressed asddvalue, expressed as 50 value, being being

100 to 600 100 to µm,wherein 600 µm, whereinthe theactive activeingredient ingredientgranulate granulateisis produced producedbybya aprocess process according to any according to any one oneofof the the preceding precedingclaims. claims.

14. 14. AnAn active active ingredientgranulate, ingredient granulate,provided provided witha acoating with coatingfor forcontrolled controlled release, release, whereinthe wherein the active active ingredient ingredient granulate is produced granulate is by aa process produced by processaccording accordingtoto any oneofofclaims any one claims 1 12. 1 to to 12.

15. 15. The The active active ingredientgranulate ingredient granulate according according to to claim claim 14, 14, wherein wherein thethe coating coating

controls therelease controls the releaseso so that that at least at least 60%,60%, preferably preferably at 70%, at least leastand 70%, in and in

particular at least particular at least 80% 80%of of thethe active active ingredient ingredient are released are released in the in theand ileum ileum in and in

the colon. the colon.

16. 16. A A use use of of anan activeingredient active ingredientgranulate, granulate,produced produced according according to to oneone of of claims claims 1 to 1 to

12, for producing 12, for producing a tablet a tablet or or capsule. capsule.

17. 17. The The useuse according according to claim to claim 16,16, wherein wherein the the tablet tablet or or capsule capsule is is coated coated with with a a controlled release controlled release coating. coating.

25 10 Jun 2025 10 Jun 2025

18. 18. The The useuse according according to claim to claim 17,17, wherein wherein the the tablet tablet or or capsule capsule releases releases at at least least

60%, preferably 60%, preferably at least at least 70% 70% and inand in particular particular at 80% at least least of 80% of the active the active

ingredient ingredient ininthe theileum ileumandand in the in the colon. colon. 2020272151

1/4 1/4

11 1 18

19

6 20 21 14 13 4 23 15 29 22 24 8 27 28 16 26 2 1 17 12 10

3 7 5 Fig. 1

2/4 2/4

Fig. 22 Fig.

Q3

[%][%] EO p3 [%]

[%] Ed

08 80 40 40

70 35

09 60 30

09 50 25

40 20

08 30 15

20 10

10 G 5

0 0 200 400 009 600 008 800 1000 [wrl] xc_min [um]

3/4 3/4

(Fig. (Fig. 3) (Fig. 3) 3)

500 um µm

4/4 4/4

(Fig. 4) (Fig. (Fig. 4) 4)

3 it 4 . : , .. X ? 18. in

"ni care ::: or ": 3 or : 3. ; 3 is . & is : A % i. in

1000 pm X , : ::